Persistent hepatitis C virus (HCV) infection is a major health problem globally affecting ˜3% of the world population and is an important contributor to chronic liver disease culminating with liver cirrhosis, hepatocellular carcinoma and liver failure [Szabo E, Lotz G, et al., Pathol. Oncol. Res., 2003, 9, 215-221; Hoofnagle J H., Hepatology, 1997, 26 15S-20]. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. In the United States alone ˜3 million are chronically infected with HCV and the number of HCV related deaths is increasing significantly over the years [Barnes E., WHO factsheet 2010. Available at: http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html]. Clinically, chronic infection is often asymptomatic with latent periods lasting for decades before manifestation by which time extensive liver damage has occurred. HCV is spread primarily by unscreened blood transfusions and use of contaminated needles and syringes; the highest risk groups are intravenous drug users and people who received blood transfusions (mainly haemophiliacs) before 1990 when screening for HCV was introduced. Factors that have been reported to influence the rate of HCV disease progression include age (increasing age is associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV co-infection (associated with a markedly increased rate of disease progression), and fatty liver.
The standard therapy for HCV was a combination of pegylated interferon (PEG-IFN) α and weight based ribavarin (RBV), which was inadequate for majority of the patients and therapy associated side effects such as pancytopenia, flu-like symptoms or depression were commonly observed leading to early treatment discontinuation [Fried M W, et al., N. Engl. J. Med., 2002, 347, 975-982]. The approval of two direct acting agents (DAA), i.e., 1st generation protease inhibitors, Incivek and Victrelis in May 2011 ushered in the era of specifically targeted HCV therapy [Jesudian A B, Gambarin-Gelwan M and Jacobson I M., Gastroenterology Hepatol. 2012, 8, 91-101].
The combination of above mentioned DAAs, PEG-IFN and RBV (triple therapy) substantially increased the rate of sustained virologic response in the treatment nave and experienced patients. However, a number of issues restrict the usage of these drugs—i) complex treatment algorithms issued by the regulatory bodies; ii) they are restricted to genotype 1; iii) low barrier to resistance mutations and/or iv) increased cost of therapy leading to only limited access to care. Hence, there exists a need for alternative therapeutic strategies that provide a broader genotype coverage, better efficacy, better tolerance and/or limited selection of resistant HCV variants.
The sequence diversity of HCV is complex with the virus organized into 6 distinct genotypes and over 100 subtypes. Additionally, HCV exists as many closely related viral sequences, termed as quasi-species, in the infected individual, making specific pharmaceutical targeting of HCV proteins challenging due to the rapid evolution of escape mutants. It is increasingly evident that a broad collection of specific, pan genotypic anti-viral drugs targeting multiple essential viral functions, in addition to the current viral therapies, will be required for effective global control of HCV.
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